Dry eyes is a widespread condition with a prevalence of approximately 14% in a recent population-based cohort (Moss S E, Klein R, and Klein B E, Archives of Ophthalmololgy 118:1264-8, 2000). Dry eyes affects people of all ages, and is most frequently observed in older patients.
Mechanisms for dry eyes include: 1) increased tear evaporation, which for example occurs in low-humidity environments or results from eye lid abnormalities with exposure of; 2) decreased tear production, which for example occurs during the use of systemic medications or results from lacrimal gland diseases; or, 3) unstable tear film, which for example occurs during contact lens wear or results from blepharitis, a common eyelid disorder. Symptoms include redness, foreign body or gritty sensation in the eye, burning sensation, and blurring of vision. The irritation may be mild or disabling. The loss of vision may be devastating.
Treatment is focused on replacing the tears, preventing their loss, and protecting the ocular surface. Artificial tears is among the most common treatment modalities aimed at replacing the aqueous tears onto the ocular surface. Artificial tears, also known as demulcents, is defined by the U.S. Food and Drug Administration as, “An agent, usually a water-soluble polymer, which is applied topically to the eye to protect and lubricate mucous membrane surfaces and relieve dryness and irritation” (Code of Federal Regulation, Title 21, Part 349, Subpart A, Section 349.3 a). Artificial tears is an aqueous balanced salt solution with an agent such as hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, and or polyvinyl alcohol.
Currently, artificial tears for public consumption are available only in a topical drop form for delivery. However, proper administration of topical drops requires an individual to recline one's head back such that the ocular surface is looking upwards towards the sky. If the head is not reclined adequately, the drop will roll off the eyelid or even completely miss the ocular surface. As a result, repeated application of drops is required until proper positioning of the ocular surface is obtained and sufficient amounts of the drops are delivered. This not only results in a waste of the artificial tears, but also is inconvenient for a user to continue to apply drops and recline his or her head until sufficient drops are delivered. Further, such a method for delivery can be difficult, particularly for the elderly, the disabled and for young children.
Liquid compositions have generally been delivered to various bodily sites in various forms including, for example, aerosol sprays and sprays delivered using electrical forces. However, the use of such sprays provides a number of drawbacks.
An aerosol or aerosol product, as referenced herein, is defined by the Code of Federal Regulations as follows, “Aerosol shall mean a material which is dispensed from its container as a mist, spray, or foam by a propellant under pressure” (Code of Federal Regulation, Title 29, Chapter 17, Part 1910, Section 1910.106). A further specification of the definition is as follows: “Aerosol product means a product characterized by a pressurized spray system that dispenses product ingredients in aerosol form by means of a propellant (i.e., a liquefied or compressed gas that is used in whole or in part, such as a co-solvent, to expel a liquid or any other material from the same self-pressurized container or from a separate container) or mechanically induced force. ‘Aerosol product’ does not include pump sprays.” (Code of Federal Regulation, Title 40, Chapter 1, Part 59, Section 59.202). In referencing the propellant, “Aerosol means any non-refillable receptacle containing a gas compressed, liquefied or dissolved under pressure, the sole purpose of which is to expel a nonpoisonous (other than a Division 6.1 Packing Group III material) liquid, paste, or powder and fitted with a self-closing release device allowing the contents to be ejected by the gas” (Code of Federal Regulation, Title 49, Chapter 1, Part 171, Section 171.8). As referenced herein, an aerosol is defined in any or all of the above terms.
Thus, an aerosol spray requires a propellant as an additional ingredient. When delivering a substance to the body for a particular purpose, it would be desirable to eliminate the use of any ingredients unnecessary for that particular purpose. Additional, unnecessary ingredients can ultimately have an adverse affect on the body. Thus, the additional ingredients must undergo rigorous tests to ensure that they will not adversely affect the body. Such tests require a substantial amount of time and money. Further, tests are not always 100% accurate and cannot possibly take into account every possible variable that may impact each and every individual. Still further, the use of additional, unnecessary ingredients adds to the cost of the compositions since additional ingredients must be obtained. In addition, the stability of the compositions can be adversely affected due to the combination of multiple ingredients. Further, additional ingredients may not always be successfully mixed with the compositions (e.g. artificial tear compositions) and, thus, tests must be performed to ensure that these ingredients will mix with and form a uniform mixture with the compositions to prevent delivery of substances having inconsistent ingredients. For example, if the composition (e.g. artificial tear composition) does not mix adequately with the additional ingredients (e.g. propellant formulation), the composition delivered may be primarily a propellant formulation at some times and primarily an artificial tear composition at other times. In fact, the U.S. Food and Drug Administration has removed certain aerosol products from the market, due to the unsafe nature of the aerosol propellant. These aerosol products with propellants include, but are not limited to, trichloroethane, vinyl chloride, and zirconium (Code of Federal Regulation, Title 21, Chapter 1, Part 216, Section 216.24). Currently, aerosol products are not permitted for ophthalmic/ocular use due to their unsafe nature because of the presence of propellant. Further, the use of aerosols may be discouraged, in general, due to potential unfavorable impact on the environment by the propellant. For these reasons and due to the delicate nature of the eye area, aerosol spray delivery of substances is not permitted for ophthalmic/ocular use.
Aerosol sprays and sprays that are delivered using, for example, piezoelectric or electromagnetic transducers are also unsafe for ophthalmic/ocular use. Such sprays deliver substances with excessive force, which would cause discomfort to the eye and could damage the delicate eye area resulting in keratopathy. As noted by MacLean, the extent of aerosol keratopathy is proportional to the force of impact of the agent onto the corneal surface (MacLean A L, American Journal of Ophthalmology 63:170919, 1967; MacLean A L, Transactions of the American Academy of Ophthalmology and Otolaryngology, 71:330-40, 1967). The keratopathy is often a mild and transient phenomenon, but can be severe, especially in patients with dry eyes whose ocular surface is abnormal and prone to easy injury.